*Pre-meds, Interns and Residents,
you're welcome too

Cancer Immunotherapy To The Rescue: Commanding The Immune System To Fight!

Written by Sahil Chopra and Mitali Adlakha

A pioneering new therapy saves the life of a woman with terminal breast cancer. Judy Perkins, an engineer from Florida was diagnosed with Stage IV breast cancer. While traditional chemotherapy and hormone therapies failed for Judy, she showed a dramatic recovery after receiving a personalized immunotherapy. Although few years ago she was just preparing to die, this experimental treatment gave her a new life. What seems like a modern-day medicine miracle is in reality a path paved by over a century of extensive scientific studies.

Immunotherapy is a revolutionary technology that uses your body’s immune system as a tool to fight cancers. The immune system is your body’s own defense mechanism against invaders such as bacteria, viruses and other pathogens. Our immune system has a number of tools in its arsenal to launch an ‘immune response’ to fight these invaders. Some of the most striking tools from your immune arsenal are the T cells, B cells, dendritic cells and other immune cells.

Cancer is a life-threatening disease and also the leading cause of death worldwide. By 2030, the estimated cancer cases per year is expected to rise to 23.6 million. Cancer occurs when certain cells in your body keep multiplying without stopping. Although, the immune system would fight these cells and stop them from spreading; yet these cancer cells can outsmart the immune system by sending signals to trick the arsenal of immune cells. Cancer cells accomplish this either by releasing factors that directly suppress the immune system or by expressing molecules on their surface that trick the immune system. Thus, Cancer cells thrive by evading the immune system.

Over the years’ scientists have developed ways to resuscitate the immune system in order to recognize and attack cancer cells more effectively than it normally would. The paradigm-shifting concept of immunotherapy was first discovered in its crudest form by a New York surgeon named Dr. William Coley. In his case studies, he made an unexpected observation that a patient with a severe streptococcal infection survived a rare form of cancer called sarcoma. Coley developed a concoction of heat-killed bacteria that later came to be called Coley’s toxins. He treated hundreds of patients over decades and concluded that the treatment worked as bacteria in the concoction would kill the cancer. Eventually due to inconsistencies in the treatment and the advent of chemotherapy and radiation, the use of Coley’s toxins to treat cancers phased out.

In the 1970s, researchers started looking back at Coley’s toxins, and made the startling revelation that it was not the bacteria in the toxins that killed the cancer, rather the immune system stimulated by the bacteria attacked the cancer cells. Once scientists realized the incredible cancer-fighting potential of the immune system, clinical trials utilizing cancer immunotherapy went mainstream and have been growing ever since.

Researchers have gathered a number of ways to unleash the versatility of the immune system. Checkpoint blockade has gained traction in the last two decades. T cells, the class of immune cells that infiltrates into cancer tissue, sometimes fail to eradicate cancers because they are suppressed by ‘checkpoints’. These checkpoints have evolved as a mechanism to repress uncontrolled immune cells, which if left unchecked would cause collateral destruction of healthy tissues in the body. Cancer cells put these checkpoints to their own use and evade the immune system. This makes the T cells feeble and cancer cells rather stronger. Checkpoint inhibitors block these suppressive immune checkpoints, thus unleashing the T cells to assault the cancer cells once again. These inhibitors have scored impressive success in recent years; anti- CTLA-4, anti-PD-1 and anti-PD-L1 being the most promising players approved by the FDA (Food and Drug Administration). In 2000, the first clinical trial of anti-CTLA-4 was performed in patients with advanced melanoma (skin cancer) which showed long term durable response, 20% patients surviving more than 4 years and a subset of patients surviving longer than 10 years. These checkpoint inhibitors and combinations of these have demonstrated considerable success in treatment of a wide variety of tumor conditions such as prostate, lung, melanoma, breast, renal, head and neck cancers and hodgkins lymphoma. These therapies have shown high response rates with a whopping 87% in the case of Hodgkins lymphoma and a rather intermediate response rate such as 15-20% in lung cancer and head and neck cancer.

Beyond checkpoint inhibitors and blockades, CAR-T cell therapy has achieved major milestones in the last two years. This therapy involves harvesting patients own T cells, genetically modifying them to kill cancer cells and infusing the modified T cells back into the body. More than 200 clinical trials utilizing CAR-T cell therapy are underway. In August 2017, FDA approved the first CAR- T cell therapy KymriahTM by Novartis for the treatment of an aggressive form of blood cancer, ALL (Acute lymphocytic leukemia) in children and young adults. Soon after in October 2017, FDA approved another CAR-T cell therapy YescartaTM by Gilead Sciences for the treatment of a rare form of blood cancer, DLBCL (Diffuse large B cell lymphoma) for adults patients. KymriahTM showed great promise in clinical trial as one single dose of the therapy left 83% of the patients cancer free after three months (52 out of 63 patients). FDA approval for YescartaTM was based on a six- month clinical trial of a single dose of the therapy in 101 patients, of which 82% patients showed improvement in their cancers and 39% saw the complete cancer disappearance after around nine months of follow-up.

On one hand, the success of these immunotherapies can sway even the skeptics, on the other hand, these new approaches have a number of challenges. While logistics, costs and recruiting patients for clinical trials are relatively minor issues, the side-effects associated with these therapies are an ultimate hurdle. Checkpoint therapy comes with side effects such as diarrhea, fever, nausea, rashes in 15-20% of the patients depending upon the dosing, timing and combinations. CAR-T cell therapy comes with potentially life-threatening side-effects. Tragically, this experimental treatment has led to the death of over five patients due to fatal neurotoxicity. Both Kymriah’s and Yescarta’s label will carry a “black box” warning of a fatal inflammatory syndrome called the cytokine release syndrome, which is caused by an over activation of the immune system and excessive release of cytokine IL-6. This can cause high grade fevers, flu-like symptoms and a potential for serious neurological damage. However formidable these side-effects seem, they are manageable by using drugs that inhibit the effects of cytokine IL-6, thus, sobering these adverse cytokine storms.

Both these therapies shed light on the quintessential modern medicine approach where science is shifting focus from protocol-based treatments to personalized therapy. Latest news stories are littered with the terrific success of a breakthrough therapy that saved the life of Judy Perkins. While conventional therapies failed for Judy Perkins, TIL or Tumor Infiltrating Lymphocyte therapy completely eradicated her previously untreatable tumor. This approach involves extracting the patient’s own T cells that infiltrate the tumor (defined as TILs) followed by a painstaking analysis to find the T cells that are most effective in killing the tumor. Once the most potent anti-tumor T cells are identified, they are amplified in the lab and infused back into the patient’s bloodstream. Till date this experimental therapy has shown promise in melanoma; nevertheless the broad applicability to other tumors such as ovarian and colorectal cancers is not far-fetched.

CAR-T cell therapy and TIL therapy inarguably favor the personalized immunotherapy approach to treat cancers. The utmost goal is to tailor the treatments to individual genetic makeup and provide state of art cure for every cancer. While these therapies are hailed as miracles, they often come with a hefty price tag. Novartis’ KymriahTM and Gilead’s YescartaTM priced at $475,000 and $373,000 per infusion respectively. It’s not just the cost of therapy, each comes with its own inexorable out-of-pocket costs.

When we begin to talk about these astronomically priced therapies we enter a debatable area: Can we put a dollar value on human life? The answer to the question always leads me to a faux-pas: Is it possible to value human lives against money? Is it your life or your money? On the other hand, Is it morally correct to ask a patient with a debilitating disease to pay a heavy price for a potentially life-saving treatment? No matter where our judgement takes us, the answers will never be satisfactory. But one thing is for sure, immunotherapy undeniably has the potential to win the war against cancer and we are heading towards a glimmering horizon by embracing the very concept of personalized immunotherapy.

Sahil Chopra is a graduate student at Weill Cornell in New York. His research focuses on developing new immunotherapies to fight metastatic ovarian cancer. He has a passion for learning latest technologies with a focus on immune related diseases. When he is not in his lab, he is either playing cricket or spending time watching documentaries.